Control of blood glucose is the cornerstone of diabetes management because glycemic control decreases the incidence and progression of diabetic complications. The implementation of rigorous regimens to control blood glucose levels in patients with diabetes mellitus has led to an increased incidence of severe iatrogenic hypoglycemic events. Unfortunately, hypoglycemia itself impairs the ability of individuals to respond appropriately to subsequent hypoglycemia - a disorder known as hypoglycemia associated autonomic failure, thus increasing the predisposition to severe hypoglycemia and its consequences. Recently an increase in mortality was observed in the highly-intensive treatment limb (targeting HbA1c values of <6%) of a multi-center clinical trial of individuals with type 2 diabetes at high risk for cardiovascular disease events. In addition, a multi-center study in the intensive care setting, demonstrated increased mortality in hyperglycemic patients randomized to highly intensive glycemic control. While the cause of the mortality in these studies could not be directly attributed to hypoglycemia, the studies raise concerns about potential indirect consequences of hypoglycemia. Because there is evidence that cardiovascular autonomic impairment is associated with, and may cause, increased mortality in diabetic and post-myocardial infarct populations, we hypothesized that antecedent hypoglycemia may impair cardiovascular autonomic function. In preliminary studies, we showed that antecedent hypoglycemia resulted in significant decreases in: (i) cardiac vagal baroreflex sensitivity (ii) the sympathetic response to a transient pharmacologically induced hypotensive stress and (iii) the sympathetic response to graded simulated orthostatic stress using lower body negative pressure. We also showed that hypoglycemia increases circulating aldosterone levels (administration of aldosterone reduces cardiovagal baroreflex sensitivity and reduces the muscle sympathetic nerve activity response). In this proposal, we wish to extend these studies to develop a mechanism based intervention to attenuate the cardiovascular autonomic changes induced by antecedent hypoglycemia. The specific aims of the proposal are to determine whether treatment with a mineralocorticoid receptor antagonist prevents: (1) attenuation of cardiovagal autonomic function in euglycemic subjects after exposure to hypoglycemia, (2) attenuation of cardiac sympathetic function in euglycemic subjects after exposure to hypoglycemia and (3) attenuation of cardiovagal baroreflex function during hypoglycemia Thus, the broad long term objectives are (1) to understand the autonomic cardiovascular consequences of hypoglycemia;(2) to determine the mechanisms involved;(3) to develop treatments to ameliorate any adverse consequences;and (4) thereby allow for safe and effective rigorous glycemic control in individuals with diabetes mellitus and critically ill patients. PUBLIC HEALTH RELEVANCE: Recent studies reveal an increase in mortality associated with intensive glycemic control. There is evidence suggesting hypoglycemia may be implicated in this increased mortality. The goals of this proposal are to (1) determine the mechanisms of and (2) develop mechanism based therapies for hypoglycemia associated cardiovascular autonomic dysfunction.